Non-biological disease modifying antirheumatic drugs (sDMARDs)
Most chronic inflammatory rheumatic diseases are characterised by a "misdirection" of the immune system. This results in a complex defence reaction against the body's own tissue, which should actually be directed against foreign organisms such as bacteria or viruses.
If this reaction is prolonged, it can result in irreversible damage to the affected organs, such as bony erosions in chronic polyarthritis (cP), fibrotic remodelling in systemic sclerosis or immune complex deposits in systemic lupus erythematosus (SLE).
Since the better understanding of autoimmune diseases, therapeutic efforts have therefore always been made to "slow down" the immune system in order to weaken the immune response and thus treat the respective clinical picture adequately. T-cells (or T-lymphocytes) play a central role in the immune response, acting as a kind of mediator between the cells that recognise the supposed foreign invader (antigen-presenting cells) and the monocytes and macrophages that are involved in the actual defence reaction.
Most of the substances listed here are aimed in one way or another at inhibiting or reducing T cells or lymphocytes in general, and also have other effects that slow down the immune system, while most biological DMARDs act very specifically on a particular cell type (e.g. B cells), molecule (e.g. abatacept) or cytokine (e.g. TNF).
The group of drugs listed here is called disease modifying anti-rheumatic drugs (DMARDs), as they directly modify the respective disease, so to speak. They are the be-all and end-all in the long-term treatment of inflammatory rheumatic diseases and should be supported by symptomatic therapy with non-steroidal analgesics (NSAIDs)/anti-inflammatory drugs from various groups, glucocorticoids if necessary and physical therapy measures. A very common term for these drugs in the past was "basic therapy", which today would be used to describe both non-biological and biological DMARDs. In contrast to NSAIDs and glucocorticoids, both are aimed less at symptomatic effects and more at long-term "suppression" or remission of the disease.
Due to their pharmacokinetics, most DMARDs require a longer period of time (weeks to months) to develop their full effect and are therefore in contrast to glucocorticoids, which initiate an excellent rapid anti-inflammatory effect. However, this immediate advantage of glucocorticoids comes at the cost of many side effects, which is why long-term high-dose glucocorticoid therapy should be avoided if possible (link to the glucocorticoids chapter). Older, now largely obsolete DMARDs such as gold or D-penicillamine are not discussed due to their rare use in rheumatic diseases.
The indications and dosages given here are merely guidelines and can of course be varied individually by the rheumatologist providing care.
Methotrexate Methotrexate (abbreviated to MTX) has dramatically improved the treatment options for cP since the mid-1980s and, despite the development of biologics, is still the most important cornerstone in the treatment of cP. MTX is also used successfully for many other inflammatory rheumatic diseases.
The exact pharmacological effect of MTX is still not fully understood, but it is known that it acts as a folic acid antagonist, increases the expression of adenosine and reduces pyrimidine synthesis and thus T cells.
In many studies, MTX has sufficiently demonstrated its efficacy in cP as well as in psoriatic arthritis, both in terms of clinical improvement and radiological progression.
In cP, MTX is recommended (with a few exceptions) as first-line therapy and treatment should be initiated immediately after diagnosis and confirmation.
The dosage regimen is once weekly orally, the initial dose is 10-15 mg/week and should then be increased to up to 30 mg/week at two- to four-week intervals, depending on response and tolerability. Since, as already mentioned, MTX acts as a folic acid antagonist, MTX therapy should be supplemented with a twice-weekly folic acid dose (2 x 5 mg).
Subcutaneous or intramuscular administration is also possible in cases of poor tolerance or swallowing problems.
However, the side effect profile of this highly potent drug must also be taken into account. Hepatotoxicity, myelosuppression (i.e. anaemia, leukopenia, thrombocytopenia), the occurrence of mucosal ulcers and the very rare methotrexate-induced pneumonitis, as well as nausea and fatigue should be emphasised. The patient must be made aware of the potential side effects before starting therapy, and regular close laboratory checks are essential, especially at the beginning of therapy.
It is important to note that MTX is also used in tumour therapy, but in a dosage up to 1000 times higher than for the treatment of cP. Patients should also be made aware of this fact and that MTX therapy in cP is by no means chemotherapy at the start of therapy.
Due to its potential teratogenicity, MTX should be discontinued one year in advance if pregnancy is planned. It is also worth mentioning that MTX has been shown to be effective not only as a monotherapy but also in combination with other conventional DMARDs and biologics. In cP, MTX therapy can be combined with chloroquine/hydroxychloroquine and sulphasalazine (O'Dell regimen).
Sulfasalazine
From a chemical point of view, sulfasalazine is a conjugate of 5-aminosalicylic acid and sulfapyridine and inhibits the arachidonic acid cascade, reduces the chemotaxis of neutrophil granulocytes and the production of proteolytic enzymes. Increased adenosine release reduces inflammation, T-cell proliferation and NK-cell and B-cell activation.
With regard to its use in the treatment of cP, it should be noted that although sulphasalazine monotherapy is likely to be inferior to MTX, it is well suited to combination therapy with MTX and chloroquine. In addition, a significant advantage over MTX is that it can also be given if the patient wishes to have children or even, under certain circumstances, during pregnancy.
Sulfasalazine is also very important in the treatment of seronegative spondyloarthropathies, where it is an excellent DMARD (also in combination with MTX if necessary).
It is administered orally and daily; the recommended dosages are between 1.5 g and 3 g/die, but can also be higher in individual cases.
Sulfasalazine also has a whole range of side effects, including nausea, dizziness, exanthema and leucopenia, which is why routine laboratory tests must be carried out during sulfasalazine therapy.
However, this substance should be avoided in the case of allergies to sulphonamides or salicylates.
Antimalarials - (hydroxy)chloroquine
As the name suggests, this group of substances originally comes from a different discipline, namely tropical medicine, where this medication is used for the prophylaxis and treatment of malaria and its pathogens, the plasmodia. There are two forms, chloroquine and hydroxychloroquine, which differ only slightly in their chemical structure. In Austria, the preparation chloroquine is mainly used, while hydroxychloroquine is favoured in other countries, especially in the English-speaking world, although there are no significant differences in terms of efficacy.
The mechanism of action of this group of substances has not yet been fully clarified, but it has been shown that the production of pro-inflammatory cytokines is inhibited.
In rheumatology, SLE is the main area of application for antimalarials, where they are particularly effective in mild forms and cutaneous forms, but can also be given in addition to other medications in more severe forms. In cP, (hydroxy)chloroquine is only recommended as a combination therapy with other DMARDs (such as MTX and/or sulphasalazine).
In terms of their side effect profile, antimalarials are clearly superior to most other DMARDs. The most feared side effect is retinal toxicity and retinal damage, which, however, are reversible if recognised early. For this reason, patients must be examined ophthalmologically before starting (hydroxy)chloroquine therapy and at six-monthly intervals thereafter. Blood count changes are less common, which is why regular laboratory checks should also be carried out, especially at the start of therapy.
The desire to have children is also not a contraindication to antimalarials, which is why they can even be given during pregnancy and breastfeeding, but only if strictly indicated.
Leflunomid
Leflunomide has been used in the treatment of cP as well as psoriatic arthritis since the late 1990s. Leflunomide is converted in the organism into its active metabolite A771726, which leads to an inhibition of dihydroorotate dehydrogenase, which in turn causes a reduction in pyrimidine synthesis. This subsequently leads to a reduction in T cells.
Multi-centre studies have shown that leflunomide has good efficacy in cP, although it is probably inferior to MTX in terms of radiological progression. Nevertheless, leflunomide has a high priority in the treatment of cP, especially in patients who cannot tolerate MTX or who have other contraindications.
It is administered once daily at a dose of 20-30 mg/die. Common side effects are increases in liver function parameters and diarrhoea. Rarely, myelosuppression may also occur, which is why close and regular laboratory checks should be carried out.
Two special features of leflunomide should be pointed out here:
Firstly, the substance is mainly metabolised via the liver, which is why, in contrast to MTX, administration is still possible in principle even in cases of severely impaired renal function.
Secondly, the half-life of the active metabolite is very long, which is why a so-called ‘wash-out’, i.e. an acceleration of the enterohepatic circulation with cholestyramine, should be carried out if side effects or toxic side effects occur or if the patient wishes to have children.
When initiating treatment with leflunomide, a possible desire to have children should also be discussed with the doctor, as leflunomide should be discontinued two years beforehand due to its teratogenicity.